Gut microbiota-derived succinate links proteostasis collapse to α-synuclein pathology and aging.

Overview

Authors: Mahmood Akbar^1,2, Sakshi Yadav², Anam Naseer^1,2, Rohil Hameed^1,2, Arunabh Sarkar², Aamir Nazir^1,2

ORCID iDs: Aamir Nazir

Institutions: Central Drug Research Institute (India); Academy of Scientific and Innovative Research (India)

Journal: iScience, volume 29, issue 6, article 115941

Dates: received 3 October 2025; accepted 27 April 2026; published online 30 April 2026

Type: Research article · Language: English

License: CC BY-NC

Identifiers: DOI 10.1016/j.isci.2026.115941 · PMID 42181274 · PMCID PMC13196573 · OpenAlex W7160107324

Open access: gold, a free copy (OpenAlex)

Status: code on request

Categories: Parkinson's (population), cellular / molecular (subfield)

Methods: Evoked potentials, Statistics

Keywords: Biological sciences

Topic: Gut microbiota and health (Molecular Biology, Biochemistry, Genetics and Molecular Biology), according to OpenAlex

Funding: Central Drug Research Institute (MLP0013, 31/004(1400)/2020-EMR-I); National Institutes of Health (P40 OD010440); Florida Atlantic University (11149, BY250); Council of Scientific & Industrial Research; University of Minnesota

Citations: not cited yet (Europe PMC); 87 references in the paper

Research resources: Anti-Alpha-synuclein antibody [MJFR1] RRID:AB_2537217, Anti-Actin antibody - Loading Control RRID:AB_302617, RRID:AB_955417, GraphPad Prism 5.01 RRID:SCR_002798, ImageJ 1.53t RRID:SCR_003070, ZEISS ZEN Microscopy Software RRID:SCR_013672

Abstract

The gut microbiome profoundly influences brain health, yet the specific microbial metabolites and mechanisms contributing to Parkinson’s disease pathology remain poorly defined. Using the Caenorhabditis elegans model expressing human α-synuclein, we systematically tested key microbial fermentation products and identified succinate as a potent driver of pathology. Succinate exposure markedly increased α-synuclein aggregation, disrupted proteostasis, and compromised mitochondrial function - manifesting as oxidative stress, reduced mitochondrial content, and attenuated UPRmt. These cellular defects led to dopaminergic neurodegeneration, locomotory impairments, and reduced lifespan, establishing succinate as a pro-neurodegenerative and pro-aging metabolite. Transcriptomic and genetic analyses revealed the involvement of nutrient-sensing pathways, prominently mTORC1, in promoting proteotoxic stress. Together, these findings highlight a direct link between microbial metabolism, proteostasis collapse, and neurodegeneration, establishing succinate as an active modulator of aging. Targeting succinate signaling mechanisms may therefore represent a tractable strategy for microbiome-based interventions in Parkinson’s disease and age-associated neurodegeneration.

Reproduced under the paper's license (CC BY-NC), from the paper cited above.

Code

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The paper's code and data availability statement is in the Data section.

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Data

Datasets cited

arrayexpress:E-MTAB-15794, at ArrayExpress; found in “Data and code availability”

Data and code availability

The RNA-seq data discussed in this publication have been deposited at ArrayExpress and are accessible through ArrayExpress accession: E-MTAB-15794 (http://www.ebi.ac.uk/arrayexpress/https://www.ebi.ac.uk/arrayexpress/E-MTAB-15794).

This paper does not report original code.

Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request.

Reproduced under the paper's license (CC BY-NC), from the paper cited above.

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Version 1, 30 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 6 authors, 1 keyword, 5 funders, 86 references, 6 RRIDs.

Cite

This paper

Akbar, M., Yadav, S., Naseer, A., Hameed, R., Sarkar, A., & Nazir, A. (2026). Gut microbiota-derived succinate links proteostasis collapse to α-synuclein pathology and aging. iScience, 29(6), 115941. https://doi.org/10.1016/j.isci.2026.115941

BibTeX

@article{akbar2026gut, author = {Akbar, Mahmood and Yadav, Sakshi and Naseer, Anam and Hameed, Rohil and Sarkar, Arunabh and Nazir, Aamir}, title = {{Gut microbiota-derived succinate links proteostasis collapse to α-synuclein pathology and aging}}, journal = {iScience}, year = {2026}, month = apr, volume = {29}, number = {6}, pages = {115941}, publisher = {Elsevier}, issn = {2589-0042}, doi = {10.1016/j.isci.2026.115941}, url = {https://doi.org/10.1016/j.isci.2026.115941}, pmid = {42181274}, pmcid = {PMC13196573} }

RIS

TY - JOUR AU - Akbar, Mahmood AU - Yadav, Sakshi AU - Naseer, Anam AU - Hameed, Rohil AU - Sarkar, Arunabh AU - Nazir, Aamir TI - Gut microbiota-derived succinate links proteostasis collapse to α-synuclein pathology and aging T2 - iScience J2 - iScience PY - 2026 DA - 2026/04/30 VL - 29 IS - 6 SP - 115941 SN - 2589-0042 PB - Elsevier DO - 10.1016/j.isci.2026.115941 UR - https://doi.org/10.1016/j.isci.2026.115941 LA - en ER -

CSL-JSON

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